Chemical Synthesis and Biological Activity of the Dogfish (Squalus acanthias) α‐melanotropins I and II, and of related peptides

The purpose of this investigation is to provide synthetic proof for the structure of dogfish (Squalus acanthias) α‐MSH and to investigate the consequences of the presence of methionine in position 13 and the lack of the N‐terminal acetyl group in this hormone. Because of the facile oxidation of methionine (13) during handling or storage, a number of specifically oxidized hormones (Met4 and Met13) as well as tripeptides belonging to the C‐terminal second message sequence were investigated. All the products were prepared by classical methods in homogeneous solution; intermediate and end products were extensively purified and characterized (Tables 3 and 4). The assays for melanotropic activity were performed in vitro with the modified reflectometric assay using the skin of Rana pipiens. It is concluded that the structures assigned to dogfish α‐MSH I and II are correct and that the isolated samples contain slight quantities of [13‐methionine (S‐oxide)]dogfish α‐MSH and [4, 13‐bis‐methionine (S‐oxide)]dogfish α‐MSH. The peptides with methionine in position 13 are as active in this assay as those containing valine. This also holds for the NH2/OH interchange distinguishing dogfish α‐MSH I from dogfish α‐MSH II. However, the lack of the N‐terminal acetyl group strongly reduces the biological activity. Its introduction into dogfish α‐MSH I results in a product that is equipotent with mammalian α‐MSH. These and other conclusions are discussed in detail.